The Role of Branched-Chain Amino Acid Supplementation in Combination with Locoregional Treatments for Hepatocellular Carcinoma: Systematic Review and Meta-Analysis.

BACKGROUND: Branched-chain amino acid (BCAA) supplementation has been linked with favorable outcomes in patients undergoing surgical or palliative treatments for hepatocellular carcinoma (HCC). To date, there has been no systematic review investigating the value of BCAA supplementation in HCC patients undergoing locoregional therapies. MATERIALS AND METHODS: A systematic search of the literature was performed across five databases/registries using a detailed search algorithm according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement. The search was conducted on March 23, 2022. RESULTS: Sixteen studies with a total of 1594 patients were analyzed. Most patients were male (64.6%) with a mean age of 68.2 ± 4.1 years, Child-Pugh score A (67.9%) and stage II disease (40.0%). Locoregional therapy consisted of radiofrequency ablation, transarterial chemoembolization or hepatic artery infusion chemotherapy. BCAA supplementation was in the form of BCAA granules or BCAA-enriched nutrient. Most studies reported improved albumin levels, non-protein respiratory quotient and quality of life in the BCAA group. Results pertaining to other outcomes including overall survival, recurrence rate, and Child-Pugh score were variable. Meta-analysis showed significantly higher levels of post-treatment serum albumin in the BCAA group (SMD = 0.54, 95% CI 0.20-0.87) but no significant differences in mortality rate (RR = 0.81, 95% CI: 0.65-1.02) and AST (SMD = -0.13, 95% CI: -0.43-0.18). CONCLUSION: BCAA supplementation is associated with higher post-treatment albumin levels. There are currently not sufficient data to support additional benefits. Further studies are needed to elucidate their value.

Evaluation of Heller's reaction and the urine dipstick method alone or in combination to detect proteinuria in sheep.

BACKGROUND: Urine dipstick and Heller's reaction are easy first-line screening tests for the detection of proteinuria; however, the performance of these methods in alkaline ovine urine is largely unknown. OBJECTIVE: The aim of this study was to evaluate the diagnostic performance of Heller's reaction alone or in combination with dipstick for the detection of proteinuria in sheep, using the urine protein to creatinine ratio (UP/C) with two cut-off values as the reference method. METHODS: Ninety-eight urine samples were collected from sheep using the transient apnea method. Heller's reaction, the dipstick method, and the UP/C ratio were used to assess proteinuria. The results were statistically analyzed twice, based on two different UP/C cut-off values of 0.2 and 0.5. Cohen's kappa value was used to determine the agreement between the UP/C ratios and Heller's reaction, the dipstick method, or the combination of methods. Sensitivity, specificity, and positive and negative likelihood ratios were calculated. ROC curves were also generated, and the areas under the curve (AUC) were evaluated to determine the optimal threshold for the numerical values of the two methods. RESULTS: Heller's reaction is more specific (96.67% and 96.00% when the cut-off value is 0.2 and 0.5, respectively) than the dipstick method, while the dipstick method was more sensitive (91.18% and 91.30%, when the cut-off value was 0.2 and 0.5, respectively) than Heller's reaction for the detection of proteinuria. Both tests were accurate when any grade >0 was considered positive. CONCLUSIONS: Proteinuria can almost be excluded in ovine urine samples with negative Heller's reaction and dipstick test.

Effect of storage time on the urine protein: creatinine ratio in alkaline ovine urine.

The urine protein:creatinine (UPC) ratio is considered the reference method to assess proteinuria. Its diagnostic value in ovine medicine needs further elucidation. In population monitoring and/or for research purposes, it is convenient to collect many samples simultaneously and store them for later analysis. However, analyte stability data are required to ensure reliable results. We used 15 of 90 urine samples collected from sheep to assess the effect of storage time on the UPC ratio. After centrifugation, the supernatant of each sample was divided into 6 aliquots. Urine protein and creatinine concentrations were determined immediately in one aliquot using the pyrogallol red and a modified Jaffè method, respectively. The other aliquots were stored at -18°C. Based on the absence of active sediment, alkaline urine pH, and UPC ratio ≥0.2, we included 15 samples in our study. The UPC ratio was determined in the stored aliquots 2, 7, 14, 21, and 60 d after collection. The data were analyzed with univariate ANOVA. No significant difference was observed in the urinary concentrations of protein, creatinine, and the UPC ratio (0.8 ± 0.84 in conventional units and 0.09 ± 0.095 in SI units) among different times (p > 0.05). The UPC ratio remained stable for 2 mo in ovine urine samples stored at -18°C.

The effect of the systemic inflammatory response on plasma zinc and selenium adjusted for albumin.

BACKGROUND & AIM: The magnitude of systemic inflammatory response, as evidenced by C-reactive protein (CRP), is a major factor associated with lower zinc and selenium. They may also be influenced by their binding proteins, such as albumin. The aim of the present study was to examine the relationships between plasma zinc, selenium and the systemic inflammatory response in a large cohort of patients referred for nutritional screen and also to examine these relationships in patients with critical illness. METHODS: Patients referred for nutritional assessment of zinc (n = 743) and selenium (n = 833) and 114 patients with critical illness were examined. Intra-assay imprecision was <10% for these analytes. RESULTS: In the nutritional screen cohort, plasma zinc was significantly associated with CRP (rs = -0.404, p < 0.001) and albumin (rs = 0.588, p < 0.001). For each CRP category (≤10, 11-80, >80 mg/l) the zinc/albumin ratio x100 was similar (31, 33 and 32 respectively, p = 0.029). Plasma selenium was significantly associated with CRP (rs = -0.489, p < 0.001) and albumin (rs = 0.600, p < 0.001). With increasing CRP category (≤10, 11-80, >80 mg/l) the selenium/albumin ratio ×100 was lower (2.3, 2.1 and 1.8 respectively, p < 0.001). Similar relationships were also observed in the cohort of patients with critical illness. CONCLUSION: Plasma zinc was associated with both CRP and albumin. The impact of the systemic inflammatory response could be largely adjusted by albumin concentrations. Plasma selenium was associated with both CRP and albumin. The impact of the systemic inflammatory response on plasma selenium concentrations could not be reasonably adjusted by albumin concentrations.

Carnitine modulates crucial myocardial adenosine triphosphatases and acetylcholinesterase enzyme activities in choline-deprived rats.

Choline is an essential nutrient, and choline deficiency has been associated with cardiovascular morbidity. Choline is also the precursor of acetylcholine (cholinergic component of the heart's autonomic nervous system), whose levels are regulated by acetylcholinesterase (AChE). Cardiac contraction-relaxation cycles depend on ion gradients established by pumps like the adenosine triphosphatases (ATPases) Na(+)/K(+)-ATPase and Mg(2+)-ATPase. This study aimed to investigate the impact of dietary choline deprivation on the activity of rat myocardial AChE (cholinergic marker), Na(+)/K(+)-ATPase, and Mg(2+)-ATPase, and the possible effects of carnitine supplementation (carnitine, structurally relevant to choline, is used as an adjunct in treating cardiac diseases). Adult male albino Wistar rats were distributed among 4 groups, and were fed a standard or choline-deficient diet for one month with or without carnitine in their drinking water (0.15% w/v). The enzyme activities were determined spectrophotometrically in the myocardium homogenate. Choline deficiency seems to affect the activity of the aforementioned parameters, but only the combination of choline deprivation and carnitine supplementation increased myocardial Na(+)/K(+)-ATPase activity along with a concomitant decrease in the activities of Mg(2+)-ATPase and AChE. The results suggest that carnitine, in the setting of choline deficiency, modulates cholinergic myocardial neurotransmission and the ATPase activity in favour of cardiac work efficiency.

Relation between riboflavin, flavin mononucleotide and flavin adenine dinucleotide concentrations in plasma and red cells in patients with critical illness.

BACKGROUND: There is some evidence that the relationship between plasma and red cell vitamin B2 concentrations is perturbed in the critically ill patient. The aim of the present study was to examine the longitudinal interrelationships between riboflavin, flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) in plasma and red cells in patients with critical illness. METHODS: Riboflavin, FMN and FAD concentrations were measured, by HPLC, in plasma and red cells in healthy subjects (n=119) and in critically ill patients (n=125) on admission and on follow-up. RESULTS: On admission, compared with the controls, critically ill patients had significantly higher plasma riboflavin and FMN concentrations (p<0.001) and lower median plasma FAD concentrations (p<0.001). In the red cell, FAD concentrations were significantly lower in critically ill patients (p<0.001). In healthy subjects, plasma riboflavin was directly associated with both plasma FMN (r(s)=0.55, p<0.001) and plasma FAD (r(s)=0.49, p<0.001). Red cell riboflavin was directly associated with red cell FMN (r(s)=0.52, p<0.001) but not red cell FAD. In the critically ill patients, plasma riboflavin was not significantly associated with either plasma FMN or FAD. Red cell riboflavin was directly associated with red cell FMN (r(s)=0.79, p<0.001) and red cell FAD (r(s)=0.72, p<0.001). Longitudinal measurements (n=60) were similar. CONCLUSIONS: The relationship between plasma riboflavin, FMN and FAD was significantly perturbed in critical illness. This effect was less pronounced in red cells. Therefore, red cell FAD concentrations are more likely to be a reliable measure of status in the critically ill patient.

Associations of acute-phase reactants with metabolic syndrome in middle-aged overweight or obese people.

BACKGROUND: Metabolic syndrome, i.e. the clustering of visceral obesity, dyslipidemia, hyperglycemia, and hypertension, has become a major public-health challenge worldwide. An acute-phase reactant is one whose level increases by 25% of the standard value during inflammation. Associations of acute-phase reactants with the components of metabolic syndrome among overweight or obese patients has rarely been examined. MATERIAL/METHODS: The CRP, ferritin, fibrinogen, haptoglobin, and ESR levels of 117 consecutive overweight or obese patients were measured. Metabolic syndrome was defined if central obesity was combined with at least two of the following factors: triglyceride level > or = 150 mg/dl or specific treatment for this abnormality, HDL cholesterol < 40 mg/dl in males and < 50 mg/dl in females or specific treatment for this abnormality, systolic/diastolic blood pressures > or = 130/85 mmHg or treatment of previously diagnosed hypertension, and fasting plasma glucose > or = 100 mg/dl or previously diagnosed type 2 diabetes. RESULTS: Eighty-two patients were characterized as having metabolic syndrome and 35 as healthy controls. CRP, haptoglobin, and ESR levels increased with increasing number of components of metabolic syndrome. Ferritin and fibrinogen, in contrast, were increased in patients with metabolic syndrome but did not correlate with the number of components. CONCLUSIONS: CRP, haptoglobin, and ESR may add significant information regarding the severity of metabolic syndrome among overweight and obese patients.

Assessment of vitamin E status in patients with systemic inflammatory response syndrome: plasma, plasma corrected for lipids or red blood cell measurements?

BACKGROUND: There is some evidence that the plasma vitamin E status is perturbed as part of systemic inflammatory response and correcting this with other plasma markers may not lead to reliable results. The aim of the present study was to examine the longitudinal inter-relationships between plasma and red blood cell vitamin alpha-tocopherol in patients with systemic inflammatory response syndrome. METHODS: alpha-tocopherol concentrations were measured, by HPLC, in plasma and red blood cells in normal subjects (n=67) and in critically ill patients with systemic inflammatory response syndrome (n=82) on admission and on follow-up. RESULTS: Plasma alpha-tocopherol was significantly lower in the critically ill patients compared with the controls (all p<0.001) with 41% of patients having concentrations below the 95% confidence interval. In contrast, when corrected for cholesterol, alpha-tocopherol concentrations were significantly higher in the critically ill patients compared with the control group (p<0.001, 27% above the 95% confidence interval) and when corrected for triglycerides, alpha-tocopherol concentrations were significantly lower in the critically ill patients compared with the control group (p<0.001). Red blood cell alpha-tocopherol corrected for haemoglobin was similar (p=0.852) in the critically ill patients compared with control subjects. The longitudinal measurements (n=53) gave similar results. CONCLUSIONS: These results indicate that there is a discrepancy between vitamin E measurements in plasma, in plasma corrected for lipids and in red blood cells. Although the value of correcting vitamin E concentrations by lipids is well established in population studies, the present study indicates that such correction is unreliable in the presence of systemic inflammatory response syndrome and that vitamin E status should be assessed using red blood cell alpha-tocopherol measurement.

[Medical-surgical integrated approach in the treatment of non-paraneoplasic hyperparathyroidism: our experience]. / Approccio integrato medico-chirurgico nel trattamento dell'iperparatiroidismonon-paraneoplastico: la nostra esperienza.

OBJECTIVE: Hyperparathyroidism is a generalized alteration of calcium, phosphorus and bone metabolism due to an increased secretion of parathyroid hormone (PTH). In addition to the paraneoplastic ectopic type, we can distinguish three eutopic types of hyperparathyroidism, i.e., the primary form, mostly due to a benign or malignant tumor of parathyroid gland, the secondary form, typical of kidney disease and tertiary form, due to the progression of secondary forms. There is not agreement, in medical literature, on the treatment of these patients. To establish the correct therapeutic approach in patients with hyperparathyroidism, we have followed a group of symptomatic subjects suffering from primary, secondary and tertiary hyperparathyroidism, taking into account the therapeutic needs. METHODS: We followed for 12 months 155 patients suffering from primary, secondary and tertiary hyperparathyroidism; 82 were in end stage kidney disease, 93 were hypertensive. Subjects with primary forms has been treated, before parathyroidectomy, with hydration (physiological solution of NaCl), bisphosphonates i.v. (pamidronate 60-90 mg in 4-6h) and, if serum calcium was higher than 12 mg/dl, loop diuretics (furosemide 40 mg/day). Subjects with secondary forms has been treated with hypo-phosphoric diet, phosphate bindings (calcium carbonate 1 g/day) and oral calcitriol (1 microg/d) before subtotal parathyroidectomy. After surgery it was administered support therapy with calcium gluconate (40 ml/day) and vitamin D (2.5mg/d) until serum calcium normalization. RESULTS: There were 55 cases of post surgery hypertensive attack treated with clonidine (300 microg/d); 8 months later there was not relapses but in all patients there was reduction of serum calcium concentration that required a substitutive treatment (calcium 1 g/day and calcitriol 1 microg/day). There was 1 case of heavy hypocalcemic state treated with calcium gluconate i.v. (40 ml/day). CONCLUSIONS: A correct approach to a non-paraneoplastic hyper-parathyroid patient need of an integration of both current medical and surgical options. In primary forms the fi rst option is the surgical approach supported by medical treatment. In secondary forms medical approach is preferable to control renal and vascular complications, while surgical therapy is to prefer in non-responders to medical therapy forms.

Imbalance of tissue inhibitors of metalloproteinases (TIMP) - 1 and - 4 serum levels, in patients with inflammatory bowel disease.

BACKGROUND: Tissue inhibitors of metalloproteinases (TIMPs) play a key role in tissue degradation and remodeling. Since chronic inflammation is associated with tissue remodeling in inflammatory bowel disease (IBD), we evaluated serum TIMP-1 and TIMP-4 levels in IBD patients, in comparison with healthy controls (HC). METHODS: TIMP-1, TIMP-2 and TIMP-4 serum levels were determined in 53 patients with ulcerative colitis (UC), 52 patients with Crohn's disease (CD) and 50 HC, by means of commercially available enzyme-linked immunosorbent assays. The levels of TIMPs were evaluated with regard to the levels of inflammatory markers, such as C reactive protein (CRP) and serum amyloid A (SAA) and the clinical characteristics of patients, so that potential correlations could be recorded. RESULTS: Mean serum TIMP-1 levels were 414.9 +/- 17.6 ng/mL in UC patients, 446.1 +/- 22.8 ng/mL in CD patients and 296.5 +/- 20.6 ng/mL in HC. UC and CD patients had significantly higher serum TIMP-1 levels when compared to HC, (p < 0.0001 in both groups). Mean serum TIMP-1 levels were significantly higher in patients with active IBD (450.5 ng/mL) in comparison with patients with inactive disease (417.3 ng/mL, p = 0.03). Moreover, males showed significantly higher mean serum TIMP-1 levels (399.8 ng/mL), compared to females (368.5 ng/mL, p = 0.04). Mean serum TIMP-2 levels did not differ between UC and CD patients or HC (p > 0.05 in all cases). Mean serum TIMP-4 levels were 1761.2 +/- 67.7 pg/mL in UC patients, 1708.1 +/- 73.4 pg/mL in CD patients and 5573.4 +/- 1246.3 pg/mL in HC. UC and CD patients had significantly lower serum TIMP-4 levels when compared to HC (p = 0.008 and p = 0.02 respectively). Mean serum TIMP-4 levels were significantly lower in males (2772.9 pg/mL), compared to females (3299.0 pg/mL, p = 0.01). In addition, CRP levels showed a statistically significant correlation with TIMP-1 (r = 0.247, p = 0.01), and TIMP-4 levels (r = 0.217, p = 0.03). Similarly, there was a statistically significant correlation between SAA levels and both TIMP-1 (r = 0.264, p = 0.008) and TIMP-4 serum levels (r = 0.212, p = 0.03). CONCLUSION: An imbalance between TIMP-1 and TIMP-4 serum levels is present in IBD patients. TIMP-1 levels could be used not only for diagnostic purposes but also for the assessment of activity in IBD. Gender tends to influence TIMP-1 and TIMP-4 serum levels. These new findings bring into question the potential role of TIMPs in IBD, thus underlining the need for future studies which could offer new insight into this matter.

Relation between pyridoxal and pyridoxal phosphate concentrations in plasma, red cells, and white cells in patients with critical illness.

BACKGROUND: Evidence suggests that the relation between plasma and red cell vitamin B-6 concentrations is perturbed as part of the systemic inflammatory response in critically ill patients. OBJECTIVE: The aim was to examine the cross-sectional and longitudinal interrelations between pyridoxal (PL) and pyridoxal phosphate (PLP) concentrations in plasma and red and white cells in patients with critical illness. DESIGN: PLP and PL concentrations were measured by HPLC in plasma and red and white cells in normal subjects (n = 126) and critically ill patients (n = 96) on admission and on follow-up. RESULTS: On admission, compared with the controls, median plasma PLP and PL (P < 0.001 and < 0.01, respectively) and red cell PLP and PL (P < 0.001 and < 0.05, respectively) and their ratio (PLP:PL) in plasma and red cells (P < 0.001 and < 0.01, respectively) were significantly lower in the critically ill. In critically ill patients, plasma PLP:PL was significantly lower than red cell PLP:PL (P = 0.001) and white cell PLP:PL (P = 0.008). Plasma PL concentration was directly associated with both red cell PL (r(s) = 0.73, P < 0.001) and white cell PL (r(s) = 0.68, P < 0.001). Red cell PL and white cell PL were directly associated with red cell PLP (r(s) = 0.82, P < 0.001) and white cell PLP (r(s) = 0.68, P < 0.001), respectively. Longitudinal measurements (n = 48) were similar. CONCLUSIONS: The relation between plasma PLP and PL was significantly perturbed in critical illness. This effect was less pronounced in red and white cells. Therefore, these results confirm the hypothesis that intracellular PLP concentrations are more likely to be a reliable measure of status than are plasma measurements in the critically ill patient.